Researchers discover why some people lose weight slower than others

Researchers at Kobe University have uncovered why some people struggle more than others to lose weight through exercise. Their study focused on mice that cannot produce specific signal molecules, which respond to short-term exercise and regulate energy metabolism. These mice consume less oxygen, burn less fat, and are more prone to weight gain. The team found a similar connection in humans, suggesting a new pathway for treating obesity.

It's commonly understood that exercise burns fat, but for some individuals, this process is more challenging, indicating that weight loss mechanisms are not simply about "calories in versus calories out."

Previous research identified a protein, PGC-1⍺, which links exercise to its effects. However, whether increased amounts of this protein directly lead to weight loss has been inconclusive. Kobe University endocrinologist Ogawa Wataru and his team discovered different versions of this protein.

Ogawa explains, “These new PGC-1α versions, called ‘b’ and ‘c,’ have almost the same function as the conventional ‘a’ version, but they are produced in muscles more than tenfold more during exercise, while the a version does not show such an increase.” His team aimed to prove that these new versions regulate energy metabolism during workouts.

To test their hypothesis, the researchers created mice lacking the b and c versions of PGC-1⍺ while retaining the standard a version. They measured muscle growth, fat burning, and oxygen consumption during rest and exercise. They also tested human subjects with and without type 2 diabetes, as insulin-intolerant and obese individuals typically have reduced levels of this molecule.

Their findings, published in the journal Molecular Metabolism, revealed that while all versions of PGC-1⍺ cause similar biological reactions, their production levels significantly impact health. The absence of the b and c versions means the body does not adapt to short-term activity, resulting in lower oxygen consumption and fat burning during and after workouts. In humans, those who produced more of the b and c versions consumed more oxygen and had less body fat, regardless of diabetes status.

“Thus, the hypothesis that the genes in skeletal muscle determine susceptibility to obesity was correct,” Ogawa summarized. However, they also found that long-term exercise increases the production of the standard a version, with mice showing increased muscle mass after six weeks of regular exercise, regardless of their ability to produce the alternative versions.

The researchers also examined the production of PGC-1⍺ versions in fat tissues, finding no significant effect from exercise. However, since animals burn fat to maintain body temperature, they investigated the mice's ability to tolerate cold. They discovered that cold exposure increases the production of the b and c versions in brown adipose tissue, and mice lacking these versions had significantly lower body temperatures. This suggests that the b and c versions may be responsible for broader metabolic adaptations to short-term stimuli.

Understanding the physiological roles of these different PGC-1⍺ versions could lead to new obesity treatments. Ogawa stated, “Recently, anti-obesity drugs that suppress appetite have been developed and are increasingly prescribed in many countries around the world.

However, there are no drugs that treat obesity by increasing energy expenditure. If a substance that increases the b and c versions can be found, this could lead to the development of drugs that enhance energy expenditure during exercise or even without exercise. Such drugs could potentially treat obesity independently of dietary restrictions.” The team is now researching the mechanisms that increase the production of the b and c versions during exercise.

This discovery highlights the complex mechanisms behind weight loss and could pave the way for more effective obesity treatments. By targeting the b and c versions of PGC-1⍺, future therapies could enhance the body's natural ability to burn fat, offering hope for those who struggle with weight management despite regular exercise.

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